The hippocampus mediates responses to affect-related behavior in preclinical models of pharmacological antidepressant efficacy, such as the forced swim test. However, the molecular mechanisms that regulate escape-directed behavior in this preclinical model of despair are not well understood. Here, using viral-mediated gene transfer, we assessed how overexpression of extracellular signal-regulated protein kinase (ERK)–2 within the dorsal hippocampus influenced behavioral reactivity to inescapable swimming stress in adult male Sprague–Dawley rats. When compared to controls, rats overexpressing hippocampal ERK-2 displayed increases in the time to initially adopt a posture of immobility, along with decreases in total time spent immobile, without influencing general locomotor activity. Collectively, the results indicate that hippocampal upregulation of ERK-2 increases escape-directed behavior in the rat forced swim test, thus providing insight into the neurobiological mechanisms that mediate antidepressant efficacy.(PsycInfo Database Record (c) 2020 APA, all rights reserved)